Bernhard Walter

Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Bavaria, Germany

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Publications (44)140.1 Total impact

  • [Show abstract] [Hide abstract] ABSTRACT: Objective: The transcription factor MITF (microphthalmia-associated transcription factor) is known to induce expression of hypoxia-inducible factor (HIF1-α), which is involved in renal carcinogenesis. The MITF p.E318K mutation leads to deficient SUMOylation of MITF, resulting in enhanced activation of its target genes. A case-control study on melanoma patients who coincidentally were affected by renal cell carcinoma (RCC) has revealed an elevated risk for mutation carriers to be affected by one or both of these malignancies, suggesting a possible role for MITF p.E318K in renal carcinogenesis. The same study described an MITF mutation frequency of 1.5% in a small cohort of sporadic RCC, but comprehensive data on sporadic renal cell tumors are missing. We therefore tested a large cohort of sporadic renal tumors for MITF p.E318K mutation status. Methods: Genomic DNA was extracted from 426 formalin-fixed, paraffin-embedded sporadic renal tumors that had been graded according to the 2004 WHO classification of renal tumors and staged according to the 2002 TNM classification. The tumor cohort was enriched with papillary and chromophobe RCC, and also contained benign oncocytomas. DNA was tested for MITF p.E318K by pyrosequencing. Results: Of 403 analyzable tumors, 402 renal tumors were wild-type ones, and only 1 case showed the MITF p.E318K mutation. This tumor was a clear-cell RCC (pT3b N0 M0 G3 according to the TNM classification 2002). The affected patient was male, 61 years old, and had no known coexisting malignancies. Conclusion: The MITF p.E318K mutation does not appear to play a major role in sporadic RCC carcinogenesis, but is possibly restricted to a rare subpopulation of inherited RCC.
    No preview · Article · Mar 2016 · Pathobiology
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    [Show abstract] [Hide abstract] ABSTRACT: Human mouse double minute 2 (Mdm2) plays an essential role in the regulation of the tumor suppressor p53. The G/G variant of SNP309 was shown to increase Mdm2 mRNA/protein expression and to be associated with an increased risk and earlier onset of different cancers in Asian populations. However, the frequency and impact of these G/G variants have not been studied in Caucasian renal cell carcinoma (RCC) patients. Therefore, we analyzed an unselected German cohort of 197 consecutive RCC patients and detected the G/G variant in 18 (9.1%) patients, the G/T variant in 116 (58.9%) patients and the T/T variant in 63 (32.0%) patients. Studying the association between age at tumor onset and SNP309 genotypes, no correlation was detected in the entire RCC cohort or among the male RCC patients. However, the female G/G patients (median age 59.5 years) were diagnosed 13.5 years earlier than the T/T females (median age 73 years). When separating all females into two groups at their median age (68 years), 7 and 1 patients with the G/G variant and 9 and 13 patients with the T/T variant were noted in these age groups (P=0.024). To study the age dependency of tumor onset further, a second, age-selected cohort of 205 RCC patients was investigated, which comprised especially young and old patients. Interestingly, the G/G type occurred more often at lower tumor stages and tumor grades compared with higher stages (P=0.039 and 0.004, respectively). In females, the percentage of the G/G variant was only slightly higher in the younger age group, whereas in males, the percentage of the G/G variant was remarkably higher in the younger age group (19.4% vs 8.0%). In summary, female Caucasian RCC patients with the MDM2 SNP309 G/G genotype showed significantly earlier tumor onset than patients with the wild-type T/T genotype.
    Full-text · Article · Feb 2016 · Oncogenesis
  • [Show abstract] [Hide abstract] ABSTRACT: Introduction: The aim of our study was to evaluate the significance of transurethral resection of the prostate (TURP) to detect prostate cancer (PCa). A comparison was performed of the TURP specimens of patients undergoing high-intensity focused ultrasound (HIFU) with the core biopsies. Materials and methods: TURP before undergoing HIFU therapy was performed in 106 patients without neoadjuvant treatment. The resected tissue was subjected to histopathological evaluation and compared to the histological results of transrectal prostate biopsy. Results: Cancer was detected in the resected tissue of 69 patients (65%). A positive correlation of the amount of resected tissue and detection of PCa could be demonstrated in a multivariate analysis. Conclusions: With a rate of 65% PCa detected by TURP, our data provide evidence that TURP might be suitable to detect PCa in a small group of selected patients with continuously rising PSA levels and several negative biopsies. On the other hand, these data underline/reinforce the necessity to treat the whole gland using modern treatment modalities such as HIFU and cryotherapy.
    No preview · Article · Feb 2013 · Urologia Internationalis
  • [Show abstract] [Hide abstract] ABSTRACT: Recent studies have underlined the role of nuclear receptors in the involvement of prostate cancer signalling pathways. A total of 84 benign prostate hyperplasia (BPH), 84 low risk prostate cancer (LPC) and 64 advanced disease (APC) cases were sampled on a tissue microarray (TMA) and stained for retinoic acid receptor (RAR)-α, retionoid X receptor (RXR)-α, liver X receptor (LXR)-α, farnesoid X receptor (FXR) and proliferate-activated receptor gamma (PPAR)-γ and the (pro)-inflammatory molecules cyclooxygenase 2 (COX2), tumor necrosis factor (TNF)-α and inducible Nitric oxide synthase (iNOS) immunohistochemically. PPAR-γ expression in APC tissues was found to be significantly higher than that in LPC and BPH specimens (p<0.001). In contrast, RXR-a expression was significantly lower (p<0.001). COX2 staining demonstrated a trend towards overexpression in APC (p=0.025). No significant differences were found for RAR-α, iNOS and TNF-α expression. Staining of FXR and LXR was seen diffusely in the cytoplasm as well as in the nucleus, preventing sufficient evaluation by definition. This study provides the basis for applying PPAR-γ ligands clinically in treatment of APC.
    No preview · Article · Aug 2012 · Anticancer research
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    [Show abstract] [Hide abstract] ABSTRACT: Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3) at different stages of prostate cancer (PCA) carcinogenesis. Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113), non-malignant prostate disease (n = 27), metastatic hormone-naive PCA (mPCA, n = 30) and castration-resistant PCA (CRPC, n = 34). Immunohistochemistry was performed to assess global levels of H4K20 methylation levels. Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy. H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.
    Full-text · Article · Mar 2012 · BMC Urology
  • [Show abstract] [Hide abstract] ABSTRACT: We studied the role of minor mismatch repair proteins (MMR) human MutL homologue 1 (hMLH1) and human MutS homologue 2 (hMSH2) in the main subtypes of renal cell carcinoma (RCC). Expression of MMR proteins hMLH1 and hMSH2 were investigated in 166 RCC tumors, containing the main subtypes by immunohistochemistry. Furthermore, each tumor was screened for microsatellite instability (MSI) using the National Cancer Institute consensus panel for hereditary non-polyposis colon carcinoma as well as for elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) by 10 additional markers. MSI was found only in 2.0% of analyzable cases and EMAST was detected only in 1 patient. hMLH1 and hMSH2 expression was reduced in 83.7 (118/141) and 51.2% (65/127) of cases, respectively, in a subtype-specific manner. None of the clear cell RCC tumors retained a high hMLH1 expression and 92.0% lost hMLH1 completely, while papillary and chromophobe RCC preserved the expression in 25.0 and 33.3% of cases (p < 0.001). Subtype specificity was also present in hMSH2 staining, where chromophobe RCC retained a high expression in 41.7% of cases, while clear cell and papillary tumors did not (29.9 and 23.1%; p = 0.01). MSI and EMAST are rare events in sporadic RCC, whereas diminished MMR protein expression is linked to tumor entity and might contribute to the different biological behavior of the RCC subtypes.
    No preview · Article · Feb 2012 · Pathobiology
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    [Show abstract] [Hide abstract] ABSTRACT: Purpose To overcome the difficulties in the interpretation of postoperative tumor obtaining biopsy cores for patients who treated their prostate cancer with high-intensity focussed ultrasound (HIFU) therapy. Methods The H&E slides of 58 patients with residual prostate cancer after HIFU treatment were systematically reviewed. Correlation between the pathologist’s findings and immunohistochemical expression of MIB-1, alpha-Methyl-Co-Racemase and 34βE-12 staining was analyzed. Results Mean time from treatment to biopsy was 40.2 (8–208) weeks. The expert review of the H&E slides identified 40 patients with viable carcinoma in the post-HIFU biopsy cores. 18 patients were revised to necrosis-only-tumors. These biopsies were performed not later than 16 weeks after HIFU treatment (median 10.9 weeks, range 8–14). Both MIB-1 and AMACR staining displayed significant differential expression in viable carcinoma (p < 0.001) compared to necrosis tumors. Referring to viable carcinoma tissue, AMACR staining index was significantly rising, the longer treatment dated back from biopsy (p < 0.002). In this context, 34-β-E12 stained negative through all tumor areas and positive in the majority (85%) of the surrounding non-neoplastic epithelium. Conclusions AMACR and MIB-1 reliably differentiate viable carcinoma from a process of ongoing irreversible necrosis in early post-HIFU prostate biopsy cores and therefore proposed—in addition with 34 beta-E12—as useful markers exposing suspicious tumor foci in difficult cases.
    Full-text · Article · Feb 2012 · World Journal of Urology
  • [Show abstract] [Hide abstract] ABSTRACT: To develop a reliable immunohistochemical marker panel differentiating between the three most common renal cell carcinoma (RCC) subtypes without inclusion of histomorphologic criteria we investigated protein expression of vimentin, glutathione S-transferase alpha (GST-α), CD10, CD117 (C-KIT), carbonic anhydrase 2 (CAII), parvalbumin, alpha-methyl-CoA-racemase (AMACR), and cytokeratin-19 (CK 19) in 65 age and stage matched trios of clear cell carcinoma, papillary renal carcinoma and chromophobe renal carcinoma using tissue microarrays. All markers displayed significant differential expression among the subtypes (p < 0.001) except CAII (p = 0.192). According to positive (LR+) and negative (LR-) likelihood ratio, six markers (CD10, GST-α, AMACR, CK19, C-KIT and arvalbumin) demonstrated acceptable or good values to detect certain subtypes of RCC, but failed in terms of ruling out the respective subtypes. Based on the individual performance of these six markers, we combined them and reviewed each single case: LR+ for detection of clear cell RCC considerably increased by application of the six marker panel, but did not exceed 10. LR- was still >0.1; in case of papillary RCC LR+ rose beyond 10, but LR- remained >0.1. LR+ for recognition of chromophobe RCC rose far beyond 10, but LR- remained >0.1. Thus, the panel can reliably recognize two main RCC subtypes without inclusion of histomorphologic features. Further improvement is needed for consistent detection of clear cell RCC and for dependably ruling out all three main subtypes as well as identification of rare variants and benign lesions like oncocytoma.
    No preview · Article · Feb 2012 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
  • [Show abstract] [Hide abstract] ABSTRACT: Somatic point mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have been identified in certain types of urological cancers, especially urothelial carcinoma of the bladder and the renal pelvis, and could be correlated with a favourable outcome. However, comprehensive data on the FGFR3 mutation status in renal cell carcinoma (RCC) are still missing. In order to investigate a possible role for FGFR3 mutations in renal cell carcinogenesis, we performed a sequence-based mutational analysis of FGFR3 in 238 primary RCC. The cohort obtained the common RCC subtypes including 101 clear cell, 50 papillary and 68 chromophobe RCC specimens. The analysed regions encompassed all FGFR3 point mutations previously described in epithelial tumours and other noncutaneous epithelial malignancies. No mutations were detected in any renal tumour type examined, and all cases showed wild-type sequence. Our results argue against an involvement of mutational activation of FGFR3 in the development of RCC. A recently described cystic renal dysplasia in a patient with thanatophoric dysplasia type 1 due to a germ line FGFR3 mutation might portend to an involvement of mutational FGFR3 activation in renal cyst formation, but this speculation needs further evaluation.
    No preview · Article · Dec 2011 · Journal of Cancer Research and Clinical Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Global histone modification patterns have been shown to be a predictive factor of recurrence in various cancers. We analyzed global histone-3-lysine-27 (H3K27) methylation in prostate cancer (PCA) tissues. H3K27 mono-, di-, and tri-methylation patterns were different in nonmalignant prostate tissue, localized PCA, metastatic PCA, and castration-resistant PCA. H3K27 mono-methylation was correlated with pT-stage, capsular penetration, seminal vesicle infiltration, and Gleason score in localized PCA and may therefore indicate adverse prognosis.
    No preview · Article · Dec 2011 · Cancer Investigation
  • [Show abstract] [Hide abstract] ABSTRACT: We enrolled 45 patients with metastatic renal cell carcinoma (RCC) at a progressive disease between March 2003 and April 2008 to assess the impact of an anti-inflammatory treatment regime in combination with metronomic low-dose chemotherapy. 42% of the patients had been systemically pre-treated. Therapy consisted of etoricoxib 60 mg daily plus pioglitazone 60 mg daily, day 1+, low-dose interferon-α 4.5 MU sc three times a week, week 1+ and low-dose capecitabine 1 g/m(2) twice daily orally for 14 days, every 3 weeks, day 1+, until disease progression. Objective response was observed in 35% of the patients (PR 27, CR 9%), which was paralleled by strong CRP decline for all patients with initially elevated CRP levels (n = 32). CRP values decreased from mean 42.3 mg/L (range 9.1-236), to 11.1 mg/L, (range 1.1-35.6), P = 0.006. Median overall survival and progression-free survival for the total cohort were 26.9 and 7.2 months for patients with elevated CRP 24.4 and 11.3 months (95% CI, 22.8-31.0/5.7-16.9) and 13.8-2.6 months (95% CI, 6.5-21.1/0.4-4.8) for the non-elevated CRP group, respectively (P = 0.082/0.017). Median observation time: 26.1 months; Overall survival at 5 years: 18%. Toxicity>WHO grade 3 was reported: Hand-foot syndrome in 16 patients (36%), diarrhea in 4, and pneumonia in 2 patients. Our data allow us to conclude that the control of tumor-associated inflammation is an important therapeutic principle in patients with metastatic RCC.
    No preview · Article · May 2011 · Medical Oncology
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    [Show abstract] [Hide abstract] ABSTRACT: Many tumor cells are characterized by a dysregulated glucose metabolism associated with increased glycolysis in the presence of oxygen ("Warburg Effect"). Here, we analyzed for the first time a possible link between glucose metabolism and immune cell infiltration in renal cell carcinoma (RCC). RCC specimens revealed a highly significant increase in the expression of lactate dehydrogenase A (LDHA) and glucose-transporter 1 (GLUT-1) compared to the corresponding normal kidney tissue on mRNA level. Accordingly, tumor cell lines of different origin such as RCC, melanoma and hepatocellular carcinoma strongly expressed LDHA and GLUT-1 compared to their nonmalignant counterparts. In line with this finding, tumor cells secreted high amounts of lactate. High expression of GLUT-1 and LDH5, a tetramer of 4 LDHA subunits, was confirmed by tissue microarray analysis of 249 RCC specimens. Overall, 55/79 (69.6%) and 46/71 (64.7%) cases of clear cell carcinoma showed a constitutive, but heterogeneous expression of GLUT-1 and LDH5, respectively. The number of CD3(+), CD8(+) and FOXP3(+) T cells was significantly elevated in RCC lesions compared to normal kidney epithelium, but effector molecules such as granzyme B and perforin were decreased in tumor infiltrating T cells. Of interest, further analysis revealed an inverse correlation between GLUT-1 expression and the number of CD8(+) T cells in RCC lesions. Together, our data suggest that an accelerated glucose metabolism in RCC tissue is associated with a low infiltration of CD8(+) effector T cells. Targeting the glucose metabolism may represent an interesting tool to improve the efficacy of specific immunotherapeutic approaches in RCC.
    Full-text · Article · May 2011 · International Journal of Cancer
  • No preview · Article · Apr 2011 · International Journal of Colorectal Disease
  • [Show abstract] [Hide abstract] ABSTRACT: To evaluate 15-year experience with patients treated with transurethral resection (TUR) of a bladder tumor (TURBT) followed by radiochemotherapy (RCT) or radiation (RT) and to describe the association of different parameters with clinical outcome. Bladder cancer patients (473) who underwent TURBT and RCT or RT with curative intent between 1982 and 2007 in our clinic were evaluated. The clinical course, operative and pathological characteristics and the long-term clinical outcome were assessed. Complete remission (CR) was achieved in 70.4% of the patients. The 5-, 10- and 15-year overall survival rates were 49%, 30% and 19%, respectively. Long-term results were significantly affected by pT stage, lymphatic vessel invasion, residual tumor status, lymph node metastasis, kind of therapy (RCT vs. RT), and the response as confirmed by restaging TUR after RCT/RT. Organ-preservation therapy in patients with bladder cancer is a valid option compared to radical cystectomy in selected patients, ideally with early-stage bladder cancer, in whom a complete transurethral resection of the tumor can be accomplished and radiochemotherapy is superior to radiation for favorable long-term outcome.
    No preview · Article · Mar 2011 · Anticancer research
  • No preview · Article · Jan 2011 · Cancer Research
  • [Show abstract] [Hide abstract] ABSTRACT: The present multi-center phase II study was designed to support the hypothesis that networking agents, which bind to ubiquitous accessible targets in metastatic castration-refractory prostate cancer (CRPC) may counteract neoplasia-specific aberrant cellular functions, thereby mediating PSA response (primary endpoint). Patients with metastatic CRPC received low-dose chemotherapy with capecitabine 1 g twice daily plus dexamethasone 1 mg daily for 14 days every 3 weeks, COX-2 blockade with rofecoxib 25 mg (or etoricoxib 60 mg) daily combined with pioglitazone 60 mg daily until disease progression. Thirty-six consecutive patients with metastatic CRPC were enrolled, of whom n = 18 (50%) had been extensively pretreated with radio- or radionuclid therapy and n = 16 (44%) with chemotherapies; n = 8 patients (22%) were medically none-fit, having an ECOG-score of 0-2. Nine of 15 patients with PSA response >50% showed objective response. Median time to PSA response was 2.4 months (range 1.0-7.3 months). Two of 9 patients responding with PSA < 4 ng/ml showed complete resolution of skeletal lesions after 9 and 16 months; 13 patients had a stable course of disease, and 5 patients experienced progressive disease. Median progression-free survival (PFS) was 4.0 months (2.8-5.1 months) and median overall survival (OS) 14.4 months (10.7-17.2 months). Toxicities according to WHO grade II were noticed in 9 patients. This new combined modular therapy approach is able to induce major responses including resolution of skeletal lesions in patients with CRPC. Furthermore, the study may clinically support the above-mentioned hypothesis.
    No preview · Article · Dec 2010 · World Journal of Urology
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    Full-text · Article · Aug 2010 · International Journal of Colorectal Disease
  • No preview · Article · Apr 2010 · European Urology Supplements
  • No preview · Article · Apr 2010 · The Journal of Urology
  • [Show abstract] [Hide abstract] ABSTRACT: The interaction among signaling networks of tumor and neighboring stroma cells in complex disease traits is poorly understood, and read-out parameters reflecting tumor-associated functional stages are scarce. A multi-centre phase II trial was designed to prove the hypothesis whether activation of presumably complementary receptor-triggered transcriptional cascades (via pioglitazone and interferon-a) could result in synergistic clinical effects. Therapy consisted of low-dose capecitabine 1 g/m2twice daily po for 14 days, every 3 weeks, day 1+, and etoricoxib 60 mg daily plus pioglitazone 60 mg daily, day 1+, and low-dose interferon-a 4.5 MU sc three times a week, week 1+, until disease progression. Fourty-five patients with renal clear cell carcinoma at a progressive disease stage and ECOG 0–2 were enrolled between March 2003 and April 2008. Forty-two percent of the patients had been systemically pretreated. Objective response was observed in 35% of the patients (PR 27%, CR 9%), which was paralleled by strong CRP decline after 4–6 weeks’ treatment. CRP values decreased from mean 42.3 mg/L, range 9.1–236, to 11.1 mg/L, range 1.1–35.6, P = 0.006. Stable disease >3 months occurred in 40%. Median overall survival and progression-free survival for the total cohort were 26.9 and 7.2 months, for CRP non-responder 13.8 and 2.6 months (95% CI, 6.5–21.1 / 0.4–4.8), and 24.4 and 11.3 months (95% CI, 22.8–31.0 / 5.7–16.9) for CRP responder, P = 0.082 / 0.017 (median observation time 26.1 months). Overall survival at 5 years was 18%. Toxicity >WHO grade 3 was reported: Hand-foot syndrome in 16 patients (36%), diarrhea in 4 patients (9%), depression in 1 patient, and pneumonia in 2 patients. (1) Clinical results of combined anti-inflammatory and angiostatic therapy were comparable with available standard therapies, although 50% of the patients had been systemically pretreated. (2) Control of tumor-associated inflammation is an important therapeutic principle in metastatic renal clear cell carcinoma. KeywordsRenal clear cell carcinoma-· C-reactive protein-· Secretome-· Metro‑nomic chemotherapy-· Pioglitazone-· Coxib-· Metastatic renal cell carcinoma-· Modular therapy-· Systems biology antiinflammatoric agents
    No preview · Chapter · Dec 2009

Publication Stats

1k Citations
140.10 Total Impact Points


  • 2012
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Department of Urology
      Erlangen, Bavaria, Germany
  • 2009-2012
    • Universitätsklinikum Erlangen
      • Department of Urology
      Erlangen, Bavaria, Germany
  • 2008
    • University Hospital Regensburg
      Ratisbon, Bavaria, Germany
    • Caritas-Krankenhaus St. Josef
      Ratisbon, Bavaria, Germany
  • 2007
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • University of Vermont
      Burlington, Vermont, United States
  • 2004-2007
    • Universität Regensburg
      • Department of Urology
      Ratisbon, Bavaria, Germany